The ecteinascidins are exceedingly potent antitumour agents isolated from the marine tunicate Ecteinascidia turbinata. Several ecteinascidins have been reported previously in the patent and scientific literature.
U.S. Pat. No. 5,256,663 describes pharmaceutical compositions comprising matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins, and the use of such compositions as antibacterial, anti-viral, and/or antitumour agents in mammals.
U.S. Pat. No. 5,089,273 describes novel compositions of matter extracted from the tropical marine invertebrate, Ecteinascidia turbinata, and designated therein as ecteinascidins 729, 743, 745, 759A, 759B and 770. These compounds are useful as antibacterial and/or antitumour agents in mammals.
U.S. Pat. No. 5,478,932 describes ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma xenografts.
U.S. Pat. No. 5,654,426 describes several ecteinascidins isolated from the Caribbean tunicate Ecteinascidia turbinata, which provide in vivo protection against P388 lymphoma, B16 melanoma, M5076 ovarian sarcoma, Lewis lung carcinoma, and the LX-1 human lung and MX-1 human mammary carcinoma xenografts.
U.S. Pat. No. 5,721,362 describes a synthetic process for the formation of ecteinascidin compounds and related structures.
WO 00/69862, from which the present application claims priority, describes the synthesis of ecteinascidin compounds from cyanosafracin B.
The interested reader is also referred to: Corey, E. J., J. Am. Chem. Soc., 1996, 118 pp. 9202–9203; Rinehart, et al., Journal of National Products, 1990, “Bioactive Compounds from Aquatic and Terrestrial Sources”, vol. 53, pp. 771–792; Rinehart et al., Pure and Appl. Chem., 1990, “Biologically active natural products”, vol 62, pp. 1277–1280; Rinehart, et al., J. Org. Chem., 1990, “Ecteinascidins 729, 743, 745, 759A, 759B, and 770: Potent Antitumour Agents from the Caribbean Tunicate Ecteinascidia turbinata”, vol. 55, pp. 4512–4515; Wright et al., J. Org. Chem., 1990, “Antitumour Tetrahydroisoquinoline Alkaloids from the Colonial Ascidian Ecteinascidia turbinata”, vol. 55, pp. 4508–4512; Sakai et al., Proc. Natl. Acad. Sci. USA 1992, “Additional antitumour ecteinascidins from a Caribbean tunicate: Crystal structures and activities in vivo”, vol. 89, 11456–11460; Science 1994, “Chemical Prospectors Scour the Seas for Promising Drugs”, vol. 266,pp. 1324; Koenig, K. E., “Asymmetric Synthesis”, ed. Morrison, Academic Press, Inc., Orlando, Fla., vol. 5, 1985,p. 71; Barton, et al., J. Chem Soc. Perkin Trans., 1, 1982, “Synthesis and Properties of a Series of Sterically Hindered Guanidine Bases”, pp. 2085; Fukuyama et al., J. Am Chem. Soc., 1982, “Stereocontrolled Total Synthesis of (+)-Saframycin B”, vol. 104,pp. 4957; Fukuyama et al., J. Am Chem Soc., 1990, “Total Synthesis of (+)-Saframycin A”, vol. 112, p. 3712; Saito, et al., J. Org. Chem., 1989, “Synthesis of Saframycins. Preparation of a Key Tricyclic Lactam Intermediate to Saframycin A”, vol. 54, 5391; Still, et al., J. Org. Chem., 1978, “Rapid Chromatographic Technique for Preparative Separations with Moderate Resolution”, vol. 43, p. 2923; Kofron, W. G.; Baclawski, L. M., J. Org. Chem., 1976, vol. 41, 1879; Guan et al., J. Biomolec. Struc. & Dynam., vol. 10 pp. 793–817 (1993); Shamma et al., “Carbon-13 NMR Shift Assignments of Amines and Alkaloids”, p. 206 (1979); Lown et al., Biochemistry, 21, 419–428 (1982); Zmijewski et al., Chem. Biol. Interactions, 52, 361–375 (1985); Ito, CRC CRIT. Rev. Anal. Chem., 17, 65–143 (1986); Rinehart et al., “Topics in Pharmaceutical Sciences 1989” pp. 613–626, D. D. Breimer, D. J. A. Cromwelin, K. K. Midha, Eds., Amsterdam Medical Press B. V., Noordwijk, The Netherlands (1989); Rinehart et al., “Biological Mass Spectrometry,” 233–258 eds. Burlingame et al., Elsevier Amsterdam (1990); Guan et al., Jour. Biomolec. Struct. & Dynam., vol. 10 pp. 793–817 (1993); Nakagawa et al., J. Amer. Chem. Soc., 111: 2721–2722 (1989); Lichter et al., “Food and Drugs from the Sea Proceedings” (1972), Marine Technology Society, Washington, D.C. 1973, 117–127; Sakai et al., J. Amer. Chem. Soc. 1996, 118, 9017; Garcia-Rocha et al., Brit. J. Cancer, 1996, 73: 875–883; and Pommier et al., Biochemistry, 1996, 35: 13303–13309; Rinehart, K. L., Med. Res. Rev., 2000, 20, 1–27 and I. Manzanares et al, Org. Lett., 2000, 2(16), 2545–2548.
The most promising ecteinascidin is ecteinascidin 743, which is undergoing clinical trials for treatment of cancers. Et 743 has a complex tris(tetrahydroisoquinolinephenol) structure of the following formula (I):

It is currently prepared by isolation from extracts of the marine tunicate Ecteinascidin turbinata. The yield is low, and alternative preparative processes have been sought.
The escteinascidins include a fused system of five rings (A) to (E) as shown in the following structure of formula (XIV):

In ecteinascidin 743, the 1,4 bridge has the structure of formula (IV):

Other known escteinascidins include compounds with a different bridged cyclic ring system, such as occurs in escteinascidin 722 and 736, where the bridge has the structure of formula (V):
escteinascidins 583 and 597, where the bridge has the structure of formula (VI):
and ecteinascidin 594 and 596, where the bridge has the structure of formula (VII):

The complete structure for these and related compounds is given in J. Am. Chem. Soc. (1996) 118, 9017–9023.
Further compounds are known with the fused five ring system. In general, they lack the bridged cyclic ring system which is present in the ecteinascidins. They include the bis(tetrahydroisoquinolinequinone) antitumor-antimicrobial antibiotics safracins and saframycins, and the marine natural products renieramicins and xestomycin isolated from cultured microbes or sponges. They all have a common dimeric tetrahydroisoquinoline carbon framework. These compounds can be classified into four types, types I to IV, with respect to the oxidation pattern of the aromatic rings.
Type I, dimeric isoquinolinequinones, is a system of formula (VIII) most commonly occuring in this class of compounds, see the following table I.
TABLE IStructure of Type I Saframycin Antibiotics SubstituentsCompoundR14aR14bR21R25aR25bR25csaframycin AHHCNOOCH3saframycin BHHHOOCH3saframycin CHOCH3HOOCH3saframycin GHOHCNOOCH3saframycin HHHCNOHCH2COCH3CH3saframycin SHHOHOOCH3saframycin Y3HHCNNH2HCH3saframycin Yd1HHCNNH2HC2H5saframycin Ad1HHCNOOC2H5saframycin Yd2HHCNNH2HHsaframycin Y2bHQbCNNH2HCH3saframycin Y2b–dHQbCNNH2HC2H5saframycin AH2HHCNHaOHaCH3saframycin AH2AcHHCNHOAcCH3saframycin AH1HHCNOHaHaCH3safraniycin AH1AcHHCNOAcHCH3saframycin AR3HHHHOHCH3aassignments are interchangeable.bwhere the group Q is of formula (IX):
Type I aromatic rings are seen in saframycins A, B and C; G and H; and S isolated from Streptomyces lavendulae as minor components. A cyano derivative of saframycin A, called cyanoquinonamine, is known from Japanese Kokai JP-A2 59/225189 and 60/084,288. Saframycins Y3, Yd1, Ad1 and Yd2 were produced by S. lavendulae by directed biosynthesis, with appropriate supplementation of the culture medium. Saframycins Y2b and Y2b-d dimers formed by linking the nitrogen on the C-25 of one unit to the C-14 of the other, have also been produced in supplemented culture medium of S. lavendulae. Saframycins AR1 (=AH2), a microbial reduction product of saframycin A at C-25 produced by Rhodococcus amidophilus, is also prepared by nonstereoselective chemical reduction of saframycin A by sodium borohydride as a 1:1 mixture of epimers followed by chromatographic separation (the other isomer AH1 is less polar). The further reduction product saframycin AR3, 21-decyano-25-dihydro-saframycin A, (=25-dihydrosaframycin B) was produced by the same microbial conversion. Another type of microbial conversion of saframycin A using a Nocardia species produced saframycin B and further reduction by a Mycobacterium species produced saframycin AH1Ac. The 25-O-acetates of saframycin AH2 and AH1 have also been prepared chemically for biological studies.
Type I compounds of formula (X) have also been isolated from marines sponges, see Table II.
TABLE IIStructures of Type I Compounds from Marine Sponges SubstituentsR14aR14bR21Rrenieramycin AOHHH—C(CH3)═CH—CH3renieramycin BOC2H5HH—C(CH3)═CH—CH3renieramycin COHOO—C(CH3)═CH—CH3renieramycin DOC2H5OO—C(CH3)═CH—CH3renieramycin EHHOH—C(CH3)═CH—CH3renieramycin FOCH3HOH—C(CH3)═CH—CH3xestomycinOCH3HH—CH3
Renieramycins A–D were isolated from the antimicrobial extract of a sponge, a Reniera species collected in Mexico, along with the biogenetically related monomeric isoquinolines renierone and related compounds. The structure of renieramycin A was initially assigned with inverted stereochemistry at C-3, C-11, and C-13. However, careful examination of the 1H NMR data for new, related compounds renieramycins E and F, isolated from the same sponge collected in Palau, revealed that the ring junction of renieramycins was identical to that of saframycins. This result led to the conclusion that the formerly assigned stereochemistry of renieramycins A to D must be the same as that of saframycins.
Xestomycin was found in a sponge, a Xestospongia species collected from Sri Lankan waters.
Type II compounds of formula (XI) with a reduced hydroquinone ring include saframycins D and F, isolated from S. lavendulae, and saframycins Mx-1 and Mx-2, isolated from Myxococcus xanthus. See table III.
TABLE IIIType II Compounds SubstituentsCompoundR14aR14bR21R25aR25bR25csaframycin DOOHOOCH3saframycin FOOCNOOCH3saframycin Mx-1HOCH3OHHCH3NH2saframycin Mx-2HOCH3HHCH3NH2
The type III skeleton is found in the antibiotics safracins A and B, isolated from cultured Pseudomonas fluorescens. These antibiotics of formula (XII) consist of a tetrahydroisoquinoline-quinone subunit and a tetrahydroisoquinolinephenol subunit.
Where R21 is —H in safracin A and is —OH in safracin B.
Saframycin R, the only compound classified as the Type IV skeleton, was also isolated from S. lavendulae. This compound of formula (XIII), consisting of a hydroquinone ring with a glycolic ester side chain on one of the phenolic oxygens, is conceivably a pro-drug of saframycin A because of its moderate toxicity.
These known compounds include the fused system of five rings of the formula (XIV):
In this text, we refer to this ring structure as the fused ecteinascidin five ring system, though it will be appreciated that the rings A and E are phenolic in the ecteinascidins and some other compounds, while in other compounds, notably the saframycins, the rings A and E are quinolic. In the compounds, the rings B and D are tetrahydro, while ring C is perhydro.